Delivery Strategies for Microbe Therapeutics

摘要 微生物疗法(MTS)是FDA监管的一类新兴药物，包括微生物区系移植， 以孢子为基础的疗法、活微生物(例如益生菌)和分泌 治疗学。目前正在对MTS进行广泛的临床试验，以治疗炎症， 病原体感染和遗传性疾病。MTS正被用于胃肠道、皮肤、 以及粘膜屏障(如口腔)。控制MT疗效的作用机制可以包括以下几个方面 微生物组调节，加强生物屏障，代谢产物或生物分泌物。这些 机制从根本上是不同的，每个机制都与不同的MT捆绑在一起。因此，我们假设 每个MT根据其作用机制、目标部位/器官和 每个单独MT的特定属性。为此，一个关键和尚未解决的挑战是确定理想 MTS的传递参数，以便可以开发和采用改进MT传递的方法。至 到目前为止，所有经过临床评估的MT都是通过最初设计和优化的技术提供的 小分子和最近在MT临床试验中的失败被归因于剂量不一致。对于其他 在药物、剂量方面，通过采用 来自工程学的制药科学和药物输送方法。我未来五年的目标是 为了：(I)了解成功提供MT的关键要求，(Ii)介绍药物科学和 以工程为基础的药物递送方法，以制定并随后改进MTS的递送；以及 (3)突出MT交付系统在使MT能够治疗影响不同疾病的疾病/障碍方面的效用 组织，如皮肤感染或胃肠道感染。我的计划将专注于定义 并随后解决特定于MT的配方和交付挑战。我们将解决以下方面的差距 与基本问题相关的知识限制了特定于MT的递送系统的合理发展 例如，在正确的地点、正确的时间和正确的剂量将MTS交付到正确的地点有多重要。我的程序 将是第一个尝试系统地提出和回答这些关键问题的人 MTS的制定和交付。

ABSTRACT Microbe therapeutics (MTs) are an emerging class of FDA-regulated drugs that include microbiota transplants, spore-based therapeutics, living microbes (e.g. probiotics), and genetically engineered bacteria that secrete therapeutics. MTs are currently being investigated in a wide-range of clinical trials to treat inflammation, pathogenic infections, and genetic disorders. MTs are being used in the gastrointestinal (GI) tract, on the skin, and on mucosal barriers (e.g. oral cavity). The mechanism of action that governs MT efficacy can range from microbiome modulation, to biological barrier reinforcement, to metabolite or biologic secretion. These mechanisms are fundamentally distinct and each one is tied to a different MT. As such, we hypothesize that each MT has distinct delivery requirements based on their mechanism of action, the target site/organ, and the specific properties of each individual MT. To this end, a key and unaddressed challenge is identifying the ideal delivery parameters for MTs so that approaches to improve MT delivery can be developed and employed. To date, all clinically evaluated MTs are delivered via technologies that were originally designed and optimized for small molecules and recent failures in MT clinical trials have been attributed to dosing inconsistencies. For other drugs, dosing has been addressed and improved through the adoption of formulation approaches from the pharmaceutical sciences and drug delivery approaches from engineering. My goals over the next five years are to: (i) understand the key requirements for successful MT delivery, (ii) introduce pharmaceutical sciences and engineering-based drug delivery approaches to formulate and subsequently improve the delivery of MTs, and (iii) highlight the utility of MT delivery systems in enabling MT treatment of diseases/disorders that affect distinct tissues, such as infections on the skin or infection in the gastrointestinal tract. My program will focus on defining and subsequently addressing the MT-specific formulation and delivery challenges. We will address gaps in knowledge that have limited the rational development of MT-specific delivery systems related to basic questions such as how important is delivery of MTs to the right place, at the right time, and at the right dose. My program will be the first to attempt a systematic approach to asking and answering these key questions towards improved formulation and delivery of MTs.